Diagnostic utility of RAS mutation testing for refining cytologically indeterminate thyroid nodules.

RAS mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of RAS mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of RAS mutation rates, risk of malignancy with RAS positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. NRAS mutations predominated at 67 % compared to HRAS (24 %) and KRAS (12 %). The malignancy rate with RAS mutations was 58 % (95 %CI=48-68 %). RAS positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among RAS-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring RAS mutation was found between subtypes. In conclusion, RAS mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common RAS-positive malignant histological subtype. See also the graphical abstract(Fig. 1).

Insights into the Mechanisms of Fetal Growth Restriction-Induced Programming of Hypertension.

In recent decades, both clinical and animal studies have shown that fetal growth restriction (FGR), caused by exposure to adverse uterine environments, is a risk factor for hypertension as well as for a variety of adult diseases. This observation has shaped and informed the now widely accepted theory of developmental origins of health and disease (DOHaD). There is a plethora of evidence supporting the association of FGR with increased risk of adult hypertension; however, the underlying mechanisms responsible for this correlation remain unclear. This review aims to explain the current advances in the field of fetal programming of hypertension and a brief narration of the underlying mechanisms that may link FGR to increased risk of adult hypertension. We explain the theory of DOHaD and then provide evidence from both clinical and basic science research which support the theory of fetal programming of adult hypertension. In addition, we have explored the underlying mechanisms that may link FGR to an increased risk of adult hypertension. These mechanisms include epigenetic changes, metabolic disorders, vascular dysfunction, neurohormonal impairment, and alterations in renal physiology and function. We further describe sex differences seen in the developmental origins of hypertension and provide insights into the opportunities and challenges present in this field.